(R)-2,5-Dimethoxy-4-Iodoamphetamine [(R)-Doi] Influences Coping Strategies to an Escapable Social Stress

Depressive mood disorders are a leading cause of disability worldwide and pharmacological treatments for these disorders are inadequate, requiring new compounds with greater efficacy be investigated. The etiology of depression is heterogeneous; however, it is well established that stress exposure, and the proinflammatory effects of stress have a major role. Psychedelic compounds have rapid and long-lasting anxiolytic and antidepressive effects in humans and animal models of stress induced affective behavior. However, it is not completely understood how these compounds produce such rapid effects. We investigated whether the psychedelic compound (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI], a selective 5-HT2A partial agonist with potent anti-inflammatory properties, influences stress-related behavior in mice exposed to repeated social aggression, and if these behavioral changes are related to the anti-inflammatory properties of this compound. Animals were subjected to the Stress Alternatives Model (SAM), an escapable social stress paradigm where animals develop either passive coping strategies like remaining in the SAM arena (Stay) with a social aggressor, or active stress coping strategies that involve utilizing the escape holes (Escape) to avoid aggression. Mice expressing these behavioral phenotypes display behaviors like those in other social aggression models that separate animals into stress-susceptible or stress-resilient groups, which have been shown to have distinct inflammatory responses to social stress. These results show that Stay and Escape animals have heightened blood plasma concentrations of the inflammatory cytokine tumor necrosis factor-α (TNF-α) compared to unstressed control mice. Additionally, these results suggest that a single administration of (R)-DOI to Stay animals in low doses, can increase active stress coping strategies such as increasing attention to the escape route, promoting escape behavior, and reducing conflict freezing in the SAM. In Escape animals, the middle-dose of (R)-DOI shifted behavior in a way that suggests it may have had acute anxiogenic effects in certain behavioral measures

Microscopic Damage Evolution During Very High Cycle Fatigue (VHCF) of Tempered Martensitic Steel

AbstractDimensioning of high-strength steels relies on the knowledge of Wöhler-type S/N data and the assumption of a fatigue limit for applications where the number of load cycles exceeds 107. Very high cycle fatigue (VHCF) experiments applied to a 0.5C-1.25Cr-Mo tempered steel (German designation: 50CrMo4) revealed surface crack initiation at prior austenite grain boundaries in medium strength condition (37HRC) and internal crack initiation at non-metallic inclusions at high strength condition (48HRC). Despite the formation of small cracks during cycling up to 109 cycles, it seems that the medium strength condition exhibits a real fatigue limit. Application of automated electron back-scattered diffraction (EBSD) within the shallow-notched area of electro-polished fatigue specimens had shown that prior austenite grain boundaries act as effective obstacles to crack propagation. High resolution thermography during cycling of the specimens allowed the identification of local plasticity, which led to crack initiation at a later stage of the fatigue life. It was found that Cr segregation rows play a decisive role in the crack initiation process. By means of high-resolution electron microscopy in combination with focused ion beam milling (FIB), evolution of cyclic plasticity and crack initiation was correlated with the material's microstructure. The results are discussed in terms of the completely different crack initiation mechanisms of medium and high strength variants of the same steel. EBSD and crack propagation data are used to adapt numerical modeling tools to predict crack initiation and short crack propagation

D3.2 Cost Concept Model and Gateway Specification

This document introduces a Framework supporting the implementation of a cost concept model against which current and future cost models for curating digital assets can be benchmarked. The value built into this cost concept model leverages the comprehensive engagement by the 4C project with various user communities and builds upon our understanding of the requirements, drivers, obstacles and objectives that various stakeholder groups have relating to digital curation. Ultimately, this concept model should provide a critical input to the development and refinement of cost models as well as helping to ensure that the curation and preservation solutions and services that will inevitably arise from the commercial sector as ‘supply’ respond to a much better understood ‘demand’ for cost-effective and relevant tools. To meet acknowledged gaps in current provision, a nested model of curation which addresses both costs and benefits is provided. The goal of this task was not to create a single, functionally implementable cost modelling application; but rather to design a model based on common concepts and to develop a generic gateway specification that can be used by future model developers, service and solution providers, and by researchers in follow-up research and development projects.<p></p> The Framework includes:<p></p> • A Cost Concept Model—which defines the core concepts that should be included in curation costs models;<p></p> • An Implementation Guide—for the cost concept model that provides guidance and proposes questions that should be considered when developing new cost models and refining existing cost models;<p></p> • A Gateway Specification Template—which provides standard metadata for each of the core cost concepts and is intended for use by future model developers, model users, and service and solution providers to promote interoperability;<p></p> • A Nested Model for Digital Curation—that visualises the core concepts, demonstrates how they interact and places them into context visually by linking them to A Cost and Benefit Model for Curation.<p></p> This Framework provides guidance for data collection and associated calculations in an operational context but will also provide a critical foundation for more strategic thinking around curation such as the Economic Sustainability Reference Model (ESRM).<p></p> Where appropriate, definitions of terms are provided, recommendations are made, and examples from existing models are used to illustrate the principles of the framework

APOBEC3G Polymorphism as a Selective Barrier to Cross-Species Transmission and Emergence of Pathogenic SIV and AIDS in a Primate Host

Cellular restriction factors, which render cells intrinsically resistant to viruses, potentially impose genetic barriers to cross-species transmission and emergence of viral pathogens in nature. One such factor is APOBEC3G. To overcome APOBEC3G-mediated restriction, many lentiviruses encode Vif, a protein that targets APOBEC3G for degradation. As with many restriction factor genes, primate APOBEC3G displays strong signatures of positive selection. This is interpreted as evidence that the primate APOBEC3G locus reflects a long-term evolutionary “arms-race” between retroviruses and their primate hosts. Here, we provide direct evidence that APOBEC3G has functioned as a barrier to cross-species transmission, selecting for viral resistance during emergence of the AIDS-causing pathogen SIVmac in captive colonies of Asian macaques in the 1970s. Specifically, we found that rhesus macaques have multiple, functionally distinct APOBEC3G alleles, and that emergence of SIVmac and simian AIDS required adaptation of the virus to evade APOBEC3G-mediated restriction. Our evidence includes the first comparative analysis of APOBEC3G polymorphism and function in both a reservoir and recipient host species (sooty mangabeys and rhesus macaques, respectively), and identification of adaptations unique to Vif proteins of the SIVmac lineage that specifically antagonize rhesus APOBEC3G alleles. By demonstrating that interspecies variation in a known restriction factor selected for viral counter-adaptations in the context of a documented case of cross-species transmission, our results lend strong support to the evolutionary “arms-race” hypothesis. Importantly, our study confirms that APOBEC3G divergence can be a critical determinant of interspecies transmission and emergence of primate lentiviruses, including viruses with the potential to infect and spread in human populations

Clinical trials of disease-modifying agents in pediatric MS Opportunities, challenges, and recommendations from the IPMSSG

Objective The impetus for this consensus discussion was to recommend clinical trial designs that can deliver high-quality data for effective therapies for pediatric patients, in a reasonable timeframe, with a key focus on short- and long-term safety. Methods The International Pediatric Multiple Sclerosis Study Group convened a meeting of experts to review the advances in the understanding of pediatric-onset multiple sclerosis (MS) and the advent of clinical trials for this population. Results In the last few years, convincing evidence has emerged that the biological processes involved in MS are largely shared across the age span. As such, treatments proven efficacious for the care of adults with MS have a biological rationale for use in pediatric MS given the relapsing-remitting course at onset and high relapse frequency. There are also ethical considerations on conducting clinical trials in this age group including the use of placeb

Current international trends in the treatment of multiple sclerosis in children:impact of the COVID-19 pandemic

Background: Only recently has the first disease-modifying therapy been approved for children with multiple sclerosis (MS) and practice patterns including substantial off-label use have evolved. Understanding attitudes towards treatment of paediatric MS and whether this has changed due to the ongoing COVID-19 pandemic is vital to guide future therapeutic trials and for developing guidelines that reflect practice. Methods: We performed an online survey within the International Paediatric Multiple Sclerosis Study Group between July and September 2020. The survey was sent to 130 members from 25 countries and consisted of five sections: demographic data, treatment, disease modifying therapies and COVID-19, outcome and three patient cases. Results: The survey was completed by 66 members (51%), both paediatric neurologists and adult neurologists. Fingolimod and β-interferons were the most frequently used disease-modifying therapies, especially among paediatric neurologists. Almost a third (31%) of respondents had altered their prescribing practice due to COVID-19, in particular at the beginning of the pandemic. Conclusions: The survey results indicate a tendency of moving from the traditional escalation therapy starting with injectables towards an early start with newer, highly effective disease modifying therapies. The COVID-19 pandemic only slightly affected prescribing patterns and treatment choices in paediatric MS

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio

Oral Pirfenidone in patients with chronic fibrosis resulting from radiotherapy: a pilot study

<p>Abstract</p> <p>Background</p> <p>Fibrosis is a common side effect after treatment with ionizing radiation. Several methods to ameliorate debilitating fibrosis have been employed but without consistent results. The goal of this pilot study is to determine if Pirfenidone, a novel regulator of cytokine gene expression, has the potential to ameliorate established radiation-induced fibrosis.</p> <p>Methods</p> <p>Open label, prospective pilot study of 800 mg three times/day, orally administered Pirfenidone was administered to enrolled patients who were had completed radiation therapy and who had established radiation-induced fibrosis. Range of motion (ROM) was assessed using standard measures, and subjective measures of pain, fatigue, disability and global health were measured every three months.</p> <p>Results</p> <p>Seven patients were enrolled of whom 3 had ROM assessments of 1 site and 2 had ROM assessments of 2 sites. Of these assessments, 6 revealed increased ROM during drug intervention while 1 revealed a decreased ROM. There was an overall improvement in the mental composite score of the SF36 while physical composite score was decreased and the vitality score was unchanged. Two patients were removed from the study because of syncopal episodes.</p> <p>Conclusion</p> <p>Several patients experienced improved function of at least 25% and reported subjective improvement. Pirfenidone may benefit patients with radiation-induced fibrosis and is worthy of a larger well controlled trial.</p

Über eine Klasse polynomialer Scharen selbstadjungierter Operatoren im Hilbertraum

HEK293A cells expressing either mouse MOG (mMOG) or rat MOG (rMOG) C terminally tagged with EGFP. (DOCX 2792 kb

Dose-Dependent Effects of the Serotonergic Psychedelic (R)-DOI are Contingent on Prior Coping Strategies to an Escapable Social Stress

Limitations of current medications for anxious and depressive mood disorders have generated interest in finding new pharmacotherapies that are more effective and produce fewer side effects. A resurgence of research into serotonergic psychedelics has recently demonstrated these drugs may have extremely valuable therapeutic potential. While serotonergic psychedelics produce temporary changes in sensory processing and behavior, psilocybin has been found to produce rapid and long-lasting (6-8 months) anti-depressive effects with single or few administrations in treatment resistant and terminally ill patients - populations particularly insensitive to current therapies. However, little is known about how psychedelics can generate such immediate and long-lasting therapeutic effects, and whether these properties are shared among other serotonergic psychedelics.Here, the therapeutic efficacy of the serotonergic psychedelic (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] was investigated in a preclinical model of repeated social stress. (R)-DOI can enhance neuronal dendrite and spine growth, but also has potent anti-inflammatory properties at extremely low doses, both of which depend on (R)-DOI binding to the 5-Hydroxytryptamine-2A-Receptor (5-HT2A). These properties may mediate potential therapeutic effects for stress-related mood disorders, as enhanced inflammatory responses and atrophy of neurons in specific stress-related brain regions have been observed in both humans and rodents displaying stress-induced dysfunctional behavior. To assess the behavioral impacts of (R)-DOI, mice were exposed to the Stress Alternatives Model (SAM), a 4-day social stress paradigm that offers the option of escape from an aggressive conspecific. By the end of day 2, animals establish either active (Escape) or passive (Stay) coping strategies in response to social stress, which generally remain unchanged for days 3 and 4 of the SAM without intervention. Immediately following day 2 of the SAM, mice were injected subcutaneously with (R)-DOI (0.3, 0.03, or 0.015 mg/kg) or saline. Results show (R)-DOI produces dose-dependent effects on stress behaviors that differ based on prior coping strategy